Ponatinib as a consolidation strategy for a second attempt at TKI discontinuation in chronic myeloid leukemia: Interim results from the restop Trial

Abstract INTRODUCTIONApproximately 30–50% of patients with chronic myeloid leukemia (CML) are eligible for tyrosine kinase inhibitor (TKI) discontinuation, of whom only 50–60% achieve sustained treatment-free remission (TFR). This rate decreases to 20–30% in published series on second TKI discontinuation attempts. The potency of the third-generation TKI ponatinib makes it a promising candidate to deepen molecular response prior to a second discontinuation attempt. METHODSResToP is a phase II, multicenter, open-label, non-comparative clinical trial that enrolled adult patients with chronic-phase CML who had previously failed a first TKI discontinuation attempt and had subsequently regained a sustained deep molecular response (MR4) for ≥1 year after restarting therapy. Patients received consolidation therapy with ponatinib 15 mg/day and acetylsalicylic acid 100 mg/day for 2 years, followed by complete treatment withdrawal. Molecular response was monitored via monthly BCR::ABL1 RT-qPCR for the first 28 weeks, then every 3 months until completing 52 weeks post-discontinuation. (NCT04160546)The primary objective of the study was to evaluate the proportion of patients maintaining a major molecular response (MMR) during the 52 weeks following ponatinib discontinuation. Secondary objectives included safety and tolerability, MR4 maintenance rate, and progression-free survival (PFS). RESULTSA total of 40 patients were enrolled between 2020 and 2022; 34 started ponatinib therapy, of whom 12 discontinued treatment early (9 due to treatment-related adverse events, and 3 due to unrelated causes). In the interim analysis, 1 patient remained on ponatinib, and 21 had entered the treatment-free phase.With a median follow-up of 49.7 weeks post-discontinuation, 85.7% of patients maintained MMR and 61.9% maintained MR4, with an overall TFR rate of 81%. No progressions to accelerated or blast phase were observed.A total of 26 patients (76.5%) reported ponatinib-related adverse events, including 17.6% with grade ≥3 events, such as 3 grade-3 cardiovascular events (stroke, myocardial infarction, and peripheral ischemia). Two of these patients had predisposing risk factors. The most frequent grade 1–2 toxicities were hypertension (14.7%), hepatotoxicity, arthralgia, and myalgia (each at 11.8%). One death unrelated to therapy was recorded. CONCLUSIONConsolidation therapy with ponatinib represents an effective and safe strategy for a second TKI discontinuation in CML patients after a prior failed withdrawal attempt.